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Targeting eIF4A1-dependent HK2 translation axis for prevention of castration-resistant prostate cancer

靶向 eIF4A1 依赖性 HK2 翻译轴预防去势抵抗性前列腺癌

基本信息

批准号：
10307097
负责人：
YIBIN DENG
金额：
$ 38.67万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307097
关键词：
5&apos Untranslated Regions AKT1 gene Ablation Androgen Receptor Androgens Binding Sites Biological CRISPR/Cas technology Cancer Etiology Cancer Patient Cancer cell line Castration Cessation of life Chemoprevention Clinical Complex Crystallization Data Deoxyglucose Development Doxycycline G-Quartets Generations Genes Genetic Genetic Models for Cancer Genetic Transcription Genetic Translation Genetic study Glucose Glucose-6-Phosphate Glycolysis Goals Hexokinase 2 Human Introns Knock-out Lentivirus Malignant neoplasm of prostate Mediating Medical Castration Messenger RNA Metastatic Prostate Cancer Molecular Mus Mutagenesis Mutation Normal Cell Occupations PTEN gene Patients Pharmaceutical Preparations Pharmacology Play Prevention Protein Biosynthesis Proteins Proto-Oncogene Proteins c-akt Publishing RNA Receptor Signaling Resistance development Role Secondary Prevention Structure System TP53 gene Testing Tissues Toxic effect Translations Tumor Suppressor Genes United States Warburg Effect androgen deprivation therapy antagonist base castration resistant prostate cancer clinical application drug development druggable target enzalutamide glucose metabolism in vivo inhibitor innovation mRNA Transcript Degradation men novel novel therapeutics patient derived xenograft model pre-clinical preclinical development prevent prostate cancer cell prostate cancer cell line prostate cancer model prostate cancer progression protein expression public health relevance side effect silvestrol small hairpin RNA standard of care translational impact tumor growth

项目摘要

Project Summary/Abstract Our overarching goal is to identify a novel mechanism-driven chemoprevention strategy that can effectively prevent or delay the development and progression of currently incurable castration-resistant prostate cancer (CRPC) to revolutionize long-term survival. In the United States, prostate cancer strikes one in six men and is the second leading cause of cancer-related deaths in men. Clinically, androgen deprivation therapy (ADT) with surgical or medical castration remains standard-of-care for advanced/metastatic prostate cancer for decades. Despite its efficacy in the short term, ADT is inevitably followed by the development of CRPC in the majority of patients. The discovery that persistent AR signaling axis plays a crucial role in CRPC led to FDA-approval of “second-generation” ADT drugs, such as the novel AR antagonist enzalutamide/Xtandi, providing 4-5 months survival benefits. However, nearly all the patients will develop resistance to these new drugs within 6 to 12 months. Thus, development of CRPC following ADT is a major clinical problem but presents a unique window for innovative secondary/tertiary chemoprevention. We demonstrate that Warburg effect caused by the elevated hexokinase 2 (HK2), which catalyzes the irreversible first step of glycolysis by phosphorylating glucose to glucose-6-phosphate (G-6-P), is required for tumor growth of CRPC. Accordingly, targeting HK2 enzymatic activity could prevent or delay CRPC. Unfortunately, current HK2 inhibitors, such as 2-deoxyglucose (2-DG), are not specific with side effects due to inhibition of ubiquitously expressed HK1, which is required for glucose metabolism of normal cells. Based on our published data and preliminary studies, we hypothesize that inhibition of HK2-mediated Warburg effect by targeting eIF4A1-dependent HK2 protein synthesis prevents or delays CRPC progression. We will test this central hypothesis by accomplishing 3 specific aims. Aim 1 is to structurally elucidate the molecular mechanism underlying eIF4A1-dependent HK2 mRNA translation in CRPC. Aim 2 is to genetically demonstrate that targeting eIF4A1 blocks HK2 mRNA translation to prevent tumor growth of CRPC in vivo; and Aim 3 is to pharmacologically demonstrate that eIF4A1specific inhibitor silvestrol blocks HK2 mRNA translation to prevent tumor growth in preclinical CRPC models. Successful accomplishment of the proposed studies will provide Proof-of-Principle that targeting eIF4A1-HK2 translation axis serves as a mechanisms-driven novel and actionable strategy to prevent CRPC progression at structural, genetic and pharmacological levels.

项目总结/摘要我们的首要目标是确定一种新的机制驱动的化学预防策略，可以有效地预防或延缓目前无法治愈的去势抵抗性前列腺癌的发展和进展（CRPC）彻底改变长期生存。在美国，前列腺癌袭击六分之一的男性，男性癌症相关死亡的第二大原因。临床上，雄激素剥夺治疗（ADT）几十年来，手术或药物去势仍然是晚期/转移性前列腺癌的护理标准。尽管ADT在短期内有效，但在大多数患者中，ADT不可避免地会发展为CRPC。患者持续性AR信号传导轴在CRPC中起关键作用的发现导致FDA批准 “第二代”ADT药物，如新型AR拮抗剂Enzalutamide/Xtandi，提供4-5个月的生存福利。然而，几乎所有的患者都会在6 - 12年内对这些新药产生耐药性。个月因此，ADT后CRPC的发展是一个主要的临床问题，但存在一个独特的窗口创新的二级/三级化学预防。我们证明了由非线性引起的瓦尔堡效应升高的己糖激酶2（HK 2），通过磷酸化催化糖酵解的不可逆的第一步葡萄糖转化为葡萄糖-6-磷酸（G-6-P）是CRPC肿瘤生长所需的。因此，针对HK 2 酶活性可以预防或延迟CRPC。不幸的是，目前的HK 2抑制剂，如2-脱氧葡萄糖，（2-DG），由于抑制普遍表达的HK 1而不是特异性的副作用，HK 1是正常细胞的葡萄糖代谢。根据我们公布的数据和初步研究，我们假设通过靶向eIF 4A 1依赖性HK 2蛋白合成抑制HK 2介导的瓦尔堡效应，或延迟CRPC进展。我们将通过实现三个具体目标来检验这个中心假设。目标1是从结构上阐明CRPC中eIF 4A 1依赖性HK 2 mRNA翻译的分子机制。目的2是从遗传学上证明靶向eIF 4A 1阻断HK 2 mRNA翻译以预防肿瘤目的3是证实eIF 4A 1特异性抑制剂司维司群在临床前CRPC模型中阻断HK 2 mRNA翻译以防止肿瘤生长。成功完成拟议研究将提供针对eIF 4A 1-HK 2翻译的原则证明轴作为一种机制驱动的新的和可行的策略，以防止CRPC进展的结构，遗传和药理水平。